Parkinson's disease (PD) is a neurodegenerative disorder in which a loss of dopamine leads to disordered signaling in the basal ganglia. While therapeutic interventions with dopamine mimetics or precursors are useful in early stages of the disease, they lose effectiveness in later stages. We hypothesize that the loss of I P effectiveness of pharmacotherapies is due to a reduction of dendritic spines on medium spiny neurons in striatum, observed both in PD as well as in animals experimentally depleted of dopamine. Spine decreases in dopamine depletion models are paralleled by increases in the number of "perforated" synapses, and by an, increase in excitatory transmission, suggesting that dopainine depletion may promote dysregulated synaptic plasticity. However, to date little is known of the signal transduction mechanisms through which dopamine regulates these processes. We hypothesize that the increased excitatory transmission initiated by dopamine depletion in the striatum leads to increased PP2B activity. This increased activity is exacerbated by a lack of control of DARPP-3 2 via the DI receptor activation, leading to PP2B and PP 1 mediated suppression of synaptic plasticity and retraction of dendritic spines. We will test this idea directly by taking both genetic and pharmacological approaches to determine the role that PP2B plays in striatal synaptic plasticity, as well as determining to what degree PP2B activity is regulated by-dopamine depletion. Using MPTP injections in mice, we will determine whether genetic inhibition of PP2B in medium spiny neurons decreases dopamine-depletion induced reductions in dendritic spine density.